DESCRIPTION (adapted from the application) Focal segmental glomerulosclerosis (FSGS) is a pathological entity of unknown etiology characterized by proteinuria, nephrotic syndrome and the progressive loss of renal function. Currently, there are limited insights into the molecular mechanisms underlying the development of FSGS. The objective of this proposal is to investigate the molecular defects associated with an inherited form of familial FSGS using positional cloning strategies. To date, we have identified over 50 multiplex, multi-generation families with evidence of Mendelian inheritance of FSGS (both autosomal dominant and recessive). We have collected and banked DNA on 543 individuals, including 114 affecteds. In preliminary studies, we established linkage to chromosome 11q21-22 in one, large, 7 generation, 399 member kindred from New Zealand (family 6530) and also demonstrated that autosomal dominant FSGS is genetically heterogeneous. In this study, this disorder will be further characterized in family 6530 through the following Specific Aims; (1) narrowing the minimal candidate region (MCR) using all available polymorphic markers and haplotype analysis and (2) identifying candidate genes and ultimately the mutation associated with FSGS in this family. After the MCR is narrowed to the smallest possible region, a yeast artificial chromosome (YAC) contig will be constructed. There are several (YAC) contigs that have been identified which span the region of interest on chromosome 11q21-22 and which are commercially available. The YAC contig will provide a framework for ordering PI artificial chromosome (PAC) and bacterial artificial chromosome (BAC) contigs. PACs and BACs will in turn be used to map expressed sequence tags (ESTs), microsatellites and genes in the MCR. The search for the mutant FSGS gene in this family will first be attempted via a candidate gene approach and subsequently through direct identification of new candidate genes using direct selection and exon trapping, if the candidate gene approach is unsuccessful. These investigations are critical to our understanding of the molecular basis of familial FSGS. Information derived from this research will also allow a better understanding of the pathogenesis of nonhereditary forms of FSGS and may provide insights regarding management of the more common idiopathic forms of this disorder.